Plant extracts for the treatment of increased bone resorption

ABSTRACT

The present invention is concerned with nutritional or pharmaceutical compositions containing an extract or concentrate of a plant from the genus  Lycopersicon.  The compositions of the invention are useful for the treatment or prophylaxis of diseases or conditions which are characterized by increased bone resorption, such as Paget&#39;s disease, tumor-induced bone disease or particularly osteoporosis.

This is a continuation of application Ser. No. 09/825,113, filed Apr. 3,2001 now abandoned, which is a continuation of the National Stage ofInternational Application No. PCT/EP99/07328, filed Oct. 4, 1999, bothof which are hereby incorporated by reference in their entirety.

The present invention relates to nutritional or pharmaceuticalcompositions comprising extracts or concentrates of plants of the genusLycopersicon and their use as inhibitors of bone resorption.

The most common metabolic bone disorder is osteoporosis. Osteoporosiscan be generally defined as the reduction in the quantity of bone,either from the reduction in bone formation or the acceleration of boneresorption, in either event the result is a decrease in the amount ofskeletal tissue. Osteoclasts (bone resorbing cells) are responsible forthe excavation of a portion of bone during the resorption process. Afterresorption, osteoblasts (bone forming cells) appear, which then refillthe resorbed portion with new bone.

In young healthy adults, the rate at which the osteoclasts andosteoblasts are formed and operate maintains a balance between boneresorption and bone formation. However, as normal consequence of aging,an imbalance in this remodeling process develops, resulting in loss ofbone. As imbalance continues over time, the reduction in bone mass andthus bone strength leads to fractures.

Many compositions and methods are described in the medical literaturefor the treatment of osteoporosis. For example, estrogens, calcitoninand bisphosphonates are known to be effective inhibitors of boneresorption.

It has now surprisingly been found that products derived from plants ofthe genus Lycopersicon (tomato) have a potent inhibitory effect on boneresorption.

The present invention therefore foresees the use of an extract orconcentrate from a plant of the genus Lycopersicon in the preparation ofa pharmaceutical or nutritional composition for the treatment orprophylaxis of a disease or condition which is characterized byincreased bone resorption, such as Paget's disease, tumor-induced bonedisease or particularly osteoporosis.

Also provided is a method for the treatment or prophylaxis of a diseaseor condition which is characterized by increased bone resorption, suchas Paget's disease, tumor-induced bone disease or particularlyosteoporosis, comprising the administration of a pharmaceutical ornutritional composition to a human or other mammal, said pharmaceuticalor nutritional composition comprising an extract or concentrate from aplant of the genus Lycopersicon, in an amount which is effective forinhibiting bone resorption.

The invention further provides the use of an extract or concentrate froma plant of the genus Lycopersicon in the preparation of a pharmaceuticalor nutritional composition for one or more indications from thefollowing group:

-   -   a) inhibiting bone resorption,    -   b) reducing the risk of developing a disease or condition which        is characterized by increased bone resorption, such as Paget's        disease, tumor-induced bone disease or particularly        osteoporosis,    -   c) for supporting the treatment of a disease or condition which        is characterized by increased bone resorption, such as Paget's        disease, tumor-induced bone disease or particularly        osteoporosis,    -   d) for supporting the treatment of osteoporosis, and    -   e) for reducing the risk of developing osteoporosis.

Further provided is a method for

-   -   a) inhibiting bone resorption,    -   b) reducing the risk of developing a disease or condition which        is characterized by increased bone resorption, such as Paget's        disease, tumor-induced bone disease or particularly        osteoporosis,    -   c) for supporting the treatment of a disease or condition which        is characterized by increased bone resorption, such as Paget's        disease, tumor-induced bone disease or particularly        osteoporosis,    -   d) for supporting the treatment of osteoporosis, and/or    -   e) for reducing the risk of developing osteoporosis        comprising the administration of a pharmaceutical or nutritional        composition to a human or other mammal, said pharmaceutical or        nutritional composition comprising an extract or concentrate        from a plant of the genus Lycopersicon, in an amount which is        effective for inhibiting bone resorption.

Osteoporosis as used herein includes osteoporosis induced by hormonedeficiency (e.g. postmenopausal) and old age, as well as secondaryosteoporosis such as osteoporosis secondary to steroid treatment orsecondary to malnutrition caused by anorexia nervosa.

Preferably the concentrate or extract is derived from a plant thebotanical species Lycopersicon esculentum (also referred to asLycopersicon lycopersicum, “tomato”), Lycopersicon pimpinellifolium(“Current tomato”), Lycopersicon hirsutum, Lycopersicon peruvianum,Lycopersicon parviflorum and/or Lycopersicon pennellii (“Fuzzy tomato”),whereby Lycopersicon esculentum is preferred.

The plant extracts and concentrates of the invention are preferablyobtained from an edible portion of the plant. By edible portion is meantthe portion which is consumed by humans in either raw or cooked form.

The extracts and concentrates of the above-mentioned plants may be inliquid form or in solid form such as in granulate or powder form.

Suitable plant concentrates are obtainable e.g. by drying orfreeze-drying the fresh-cut plants or the respective roots, fruits orseeds thereof and then optionally grinding or granulating the driedmaterial; or by squeezing the fresh-cut plants or the respective roots,fruits or seeds thereof and gathering the liquid fraction and optionallydrying it, or by cooking the fruit until a concentrated thickened pasteis obtained. The use of a concentrate of the above-mentioned plants insolid form and particularly in powder form is preferred, however, alsocommercial forms such as tomato juice, ketchup, tomato sauce or tomatopaste are useful plant concentrates according to the invention.

Suitable methods of obtaining extracts of the above-mentioned plants areknown in the art. The plant extracts are obtainable e.g. by extractingthe fresh-cut or dried plants or the respective roots, fruits or seedsthereof for example with water or with one or more food grade solventsor with a mixture of water and one or more food grade solvents. Suitablefood grade solvents include propane, butane, butyl acetate, ethylacetate, ethanol, carbon dioxide, acetone, nitrous oxide, methanol andpropan-2-ol, whereby ethanol and carbon dioxide are preferred; ethanolis a particularly preferred food grade solvent. After the extractionstep the liquid phase is optionally concentrated or dried by evaporationor freeze drying. The fresh-cut or dried plant material may beintroduced in cold or preferably hot water and/or solvent, preferablywater or a mixture of water with one or more solvents, for a specifiedperiod of time, which may vary within wide ranges depending on the kindof plant material or solvent used but commonly amounts for example to 1to 30 minutes, preferably 2 to 15 minutes and most preferred 5 to 10minutes for a water extraction and for example 30 to 90 minutes,preferably 60 minutes for an ethanol/water extraction. For a waterextraction the temperature preferably lies in the range of 85 to 95° C.and for an alcohol/water extraction the temperature preferably lies inthe range of 55 to 65° C. For a carbon dioxide extraction, theextraction preferably takes place at 0 to 40° C. and at super-criticalpressure (e.g. 80-200 bar). After the extraction the liquid phase isseparated and advantageously concentrated or evaporated to drynessaccording to known methods. To obtain a concentrated extract two or moreextraction steps as described above may be combined. Moreover, the plantextracts may be obtained by introducing the fresh-cut or dried plant inwater and subjecting the mixture to a steam distillation. The distillateis collected and is then advantageously concentrated or evaporated todryness.

The extract may be used in liquid form, particularly in aqueous form, orin solid form, particularly in granulate or powder form. If the extractis in liquid form, it has a solid contents of for example from 1 to 25%by weight, preferably from 2 to 20% by weight and most preferred from 2to 15% by weight.

The amount of inventive plant extract or concentrate to be supplied mayvary within wide ranges, depending on i.a. the desired treatment,subject to be treated and his needs. Thus, where the subject to betreated is an adult person (typically of ca. 60 to 75 kg body weight), asatisfactory inhibitory effect on bone resorption is, in generalobtained with compositions formulated to allow a daily administration of0.1 to 20 grams, preferably 0.2 to 15 grams, and most preferred 0.4 to10 grams of plant concentrate or extract (on a solvent-free basis).

Suitable nutritional compositions comprising the above-mentioned plantextracts or concentrates represent a further object of the invention.They are characterized in that they comprise

(a) at least one extract or concentrate from a plant of the genusLycopersicon,

(b) a calcium source, and optionally

(c) at least one energy source selected from the group consisting ofcarbohydrate, fat and nitrogen sources, and optionally

(d) Vitamin D.

The term nutritional compositions as used herein comprises i.a.:

-   -   i) Dietary foods for special medical purposes (hereinafter        “medical nutrition”) which means a category of foods for        particular nutritional uses specially processed or formulated        and intended for the dietary management of patients and to be        used under medical supervision which are intended for exclusive        or partial feeding of patients with a limited, impaired or        disturbed capacity to take, digest, absorb, metabolise or        excrete ordinary foodstuffs or certain nutrients contained        therein or metabolites, or with other medically determined        nutrient requirements, whose dietary management cannot be        achieved only by modification of the normal diety, by other        foods for particular nutritional uses or by a combination of the        two. These foods are either nutritionally complete foods with a        nutrient-adapted formulation specific for a disease, disorder or        medical condition which, used in accordance with the        manufacturer's instructions, may constitute the sole source of        nourishment for the persons for whom they are intended or they        may be nutritionally incomplete foods with a nutrient-adapted        formulation for a disease, disorder or medical condition which        are not suitable to be used as the sole source of nourishment        and are thus used as a partial replacement or as a supplement to        the patient's diet;    -   ii) Food products which are likely to be classified as        “functional foods”, i.e. foods that are similar in appearance to        conventional foods and are intended to be consumed as part of a        normal diet or a supplement, but have been modified to        physiological roles beyond the provision of simple nutrient        requirements. The term food products is intended to cover the        whole variety of foods and beverages, including but not limited        to yoghurts, ice creams, cheeses, baked products such a fresh or        frozen bread, crisp bread, crisp bread sandwiches, biscuits and        cakes, dairy and dairy substitute foods, desserts, confectionary        products, edible oil compositions, spreads, cereal and/or fruit        bars, breakfast cereals, savoury snacks, juices, soups, ketch-up        and the like.

Preferred nutritional compositions comprise component (c) as a mandatoryingredient. Particularly preferred nutritional compositions compriseboth component (c) and (d) as mandatory ingredients.

Regarding component (a), the definitions, preferences and amounts givenbefore for the extracts and concentrates of a plant from the genusLycopersicon apply. It is also possible to have a mixture of two or moreof said plant extracts and concentrates as component (a). Thenutritional compositions of the invention conveniently comprise (in % byweight) for example from approximately 0.1 to 40%, preferably fromapproximately 3 to 25% and most preferred from 5 to 15% of plant extractor concentrate component (a).

The calcium source (b) may comprise any physiological acceptableinorganic or organic compound containing calcium. Examples are inorganiccalcium salts, for example calcium chloride, calcium phosphate, calciumsulfate, calcium oxide, calcium hydroxide or calcium carbonate, ororganic calcium components like whole or skim milk powder, calciumcaseinate or calcium salts of organic acids such as calcium citrate,calcium maleate, or mixtures thereof. The use of organic calciumcompounds, particularly skim milk powder, calcium caseinate or mixturesthereof, as calcium source (b) is preferred. The amount of calciumcomponent to be supplied may vary within wide ranges. In general, theinventive compositions comprise in one unit dosage from about 100 mg to1000 mg, preferably 200 mg to 700 mg and most preferred 300 to 600 mg ofcalcium (on an elemental basis).

The nutritional compositions of the invention conveniently comprise (in% by weight) for example from approximately 1 to 60%, preferably fromapproximately 5 to 50% and most preferred from 10 to 40% of calciumcomponent (b).

Suitable carbohydrate sources include for example maltodextrins, starch,lactose, glucose, sucrose, fructose, xylit and/or sorbit. In these formsthe carbohydrates are both energy suppliers and sweeteners. Theinventive compositions may contain one or more different carbohydratesources.

Suitable fat sources include omega-6 polyunsaturated fatty acid sources,omega-3 polyunsaturated fatty acid sources, mono-unsaturated fatty acidsources, medium chain fatty acid sources (i.e. C₆-C₁₂-fatty acids); ormixtures thereof. The above-mentioned fatty acids may be employed ineach case in form of the free acid, in mono-, di- or particularly intriglyceride form, or in form of a pharmacological or nutritionalacceptable natural source.

Suitable natural sources of omega-6 polyunsaturated fatty acids includevegetable oils such as safflower oil, sunflower oil, soya oil, cottonoil and corn oil. Suitable natural sources of omega-3 polyunsaturatedfatty acids include linseed oil and fish oils such as menhaden oil,salmon oil, mackerel oil, tuna oil codliver oil and anchovy oil.

Suitable natural sources of mono-unsaturated fatty acid sources areparticularly omega-9 mono-unsaturated fatty acids, for example olives,canola, safflower (hybrids) and sunflower (hybrids).

A preferred fat source comprises triglyceride oils supplying the desiredamounts of omega-6 polyunsaturated fatty acids and omega-3polyunsaturated fatty acids and which are rich in the medium chain fattyacid residues (i.e. residues of C₆-C₁₂ fatty acid) and/ormono-unsaturated fatty acid residues. The inventive compositions maycontain one or more different fat sources.

Examples of suitable nitrogen sources of the inventive nutritionalcompositions include sources containing nutritionally acceptableproteins such as soy bean derived proteins; milk proteins such as wheyproteins or caseinates; and/or protein hydrolysates; and/or essentialamino acids mixtures in free amino acid form or salt form; and/orcompounds associated with the synthesis of polyamines, such as arginine,arginine precursors, ornithine and the like, in free amino acid form orsalt form.

Preferred nitrogen sources of the nutritional compositions are

(i) soy bean derived proteins, which may be employed in the form of soybeans or in the form of any suitable soja extract or concentrate, forexample in form of soy flour, dried soy sprouts, soybean milk, or asdried aqueous extract from soybeans; or

(ii) milk proteins, for example whey derived proteins or caseinateswhich may be employed for example in the form of whey powder, caseinatesalts such as calcium caseinate and/or whole or preferably skim milkpowder and/or

(iii) a mixture of essential amino acids and/or

(iv) arginine as nitrogen source.

Milk proteins such as whey powder, caseinates, particularly calciumcaseinate, and/or skim milk powder are another particularly preferrednitrogen source of the claimed nutritional compositions. The inventivecompositions may contain one or more different nitrogen sources.

The nutritional compositions comprise (in % by weight) for example, fromapproximately 0.1% to 98.9%, preferably from approximately 1 toapproximately 95%, and most preferred from 10 to 90% of energy sourcecomponent (c).

The contribution of the nitrogen source, carbohydrate source and fatsource to the caloric of the inventive nutritional compositions may varywithin wide ranges. For example, the carbohydrate source provides for 30to 70% of the total energy supply, the nitrogen source for 5 to 45%,preferably 5 to 40%, and the fat source for 0.1 to 15%, or 0.01 to 5%,of the total energy supply of the composition. In preferred compositionsof the invention the carbohydrate source provides for 40 to 60% of thetotal energy supply, the nitrogen for 20 to 35% and the fat source for 3to 12% of the total energy supply of the composition.

A preferred energy source (c) of the inventive compositions comprises 30to 70% of the total energy supply of one or more carbohydrate sourcesselected from the group consisting of maltodextrins, starch, lactose,glucose, sucrose, fructose, xylit and sorbit;

5 to 45% of the total energy supply of one or more nitrogen sourcesselected from the group consisting of soy bean derived proteins, milkproteins, a mixture of essential amino acids and arginine and

0.1 to 15% of the total energy supply of one or more fat sourcescomprising omega-3- and omega-6-polyunsaturated fatty acids.

A particularly preferred energy source (c) of the inventive compositionscomprises 40 to 60% of the total energy supply of one or morecarbohydrate sources selected from the group consisting ofmaltodextrins, starch, lactose, glucose, sucrose, fructose, xylit andsorbit; 20 to 35% of the total energy supply of one or more nitrogensources selected from the group consisting of soy bean derived proteins,skim milk powder and caseinates; and 3 to 12% of the total energy supplyof one or more fat sources comprising omega-3- andomega-6-polyunsaturated fatty acids.

The amount of Vitamin D (optional component (d)) to be supplied may varywithin wide ranges. In general, the inventive compositions comprise inone unit dosage from about 50 IU to 1000 IU, preferably about 100-500 IU(more particularly preferred about 500 IU for a medical nutritionproduct and about 200 IU for a functional food product).

The nutritional compositions of the invention may comprise othernutritionally acceptable components such as vitamins, minerals, traceelements, fibers (preferably soluble fibers), flavors, preservatives,colorants, sweeteners, emulsifiers and the like.

Examples of vitamins suitable for the incorporation in the compositionof the invention include Vitamin A, Vitamin D, Vitamin E, Vitamin K,Vitamin C, folic acid, thiamin, riboflavin, Vitamin B₆, Vitamin B₁₂,niacin, biotin and panthotenic acid in pharmaceutical or nutritionallyacceptable form.

Examples of mineral elements and trace elements suitable for theincorporation in the composition of the invention include sodium,potassium, phosphorous, magnesium, copper, zinc, iron, selenium,chromium and molybdenum in pharmaceutical or nutritionally acceptableform.

The term soluble fiber as used herein refers to fibers which are able tosubstantially undergo fermentation in the colon to produce short chainfatty acids. Examples of suitable soluble fibers include agar-agar,alginates, carubin, carrageenan, gum arabic, guar gum, karaya gum,locust bean gum, pectin, tragacanth, cereal beta-glucan or xanthan gum.They may be hydrolysed or not.

Suitable flavors include natural or artificial flavors, for examplefruit flavors such as banana, orange, peach, pineapple or rasberry;vegetable flavors; or vanilla, cocoa, chocolate, coffee and the like.

Preferred ingredients of the inventive nutritious compositions inaddition to components (a), (b), (c) and (d) comprise beta-carotene(Vitamin A), Vitamin E, Vitamin C, thiamin, Vitamin B₁, B₆ and/or B₁₂,potassium, magnesium, selenium, zinc, phosphorous and soluble fiber inpharmaceutical or nutritionally acceptable form.

The nutritional compositions may comprise (in % by weight) for example,from approximately 0.1% to 15%, preferably from approximately 0.2 toapproximately 10%, and most preferred from 0.5 to 5% of these additionalcomponents other than components (a), (b), (c) and optionally (d).

The nutritional compositions defined as medical nutrition may beformulated and administered in any form suitable for enteraladministration, for example oral administration or tube feeding, e.g.nasal administration. The medical nutrition compositions areconveniently administered in the form of an aqueous liquid. The medicalnutrition compositions suitable for enteral application are accordinglypreferably in aqueous form or in powder or granulate form, whereby thepowder or granulate is conveniently added to water prior to use. For useas tube feeding, the amount of water to be added will i.a. depend on thepatient's fluid requirements and condition.

The inventive medical nutrition compositions may be in form of acomplete formula diet (in liquid or powder form), such that, when usedas sole nutrition source essentially all daily caloric, nitrogen, fattyacids, vitamin, mineral and trace element requirements are met. Ingeneral, the daily amount to be supplied to adult persons will lie inthe range of 750 to 3500 kcal/day, in particular of 1000 to 2000kcal/day. However, the inventive medical nutrition compositions arepreferably intended for use as a medical nutrition supplement. Theamount of energy supplied by a supplement should not be too excessive,in order not to unnecessarily suppress the patients appetite. Thesupplement conveniently comprises energy sources in an amount supplyingfrom 50 to 1500 kcal/day, preferably 100 to 900 kcal/day and mostpreferred 150 to 700 kcal/day.

Preferred functional foods according to the invention as definedhereinbefore are drinks (vegetable or juice), savoury snacks (such assavoury cereal bars and extruded snacks) and spreads which may beobtained in a manner known per se.

The nutritional compositions of the invention which are in liquid form,for example in drink form, or preferably in solid form, for example ingranulate or powder form, may be obtained in a manner known per se, e.g.by admixing the ingredients and optionally adding water.

The invention further relates to pharmaceutical compositions in singledose unit form comprising

(a) at least one extract or concentrate from a plant of the genusLycopersicon, and

(b) a pharmaceutical acceptable carrier.

These pharmaceutical compositions are compositions for enteraladministration, such as oral, nasal or rectal administration. Suitablepharmaceutical compositions may be in liquid form or preferably in solidform and comprise (in % by weight) for example, from approximately0.001% to 100%, preferably from approximately 0.1 to approximately 50%,active ingredient (a).

The active ingredient (a) is an extract or concentrate from a plant ofthe genus Lycopersicon where the above-given definitions and preferencesapply. It is also possible to have a mixture of two or more of saidplant extracts and concentrates a).

Pharmaceutical compositions for enteral administration are, for example,those in single dose unit forms, such as dragées, tablets, capsules orsachets. They are prepared in a manner known per se, for example bymeans of conventional mixing, granulating, confectioning, dissolving orlyophilising processes.

For example, pharmaceutical compositions for oral administration can beobtained by combining the active ingredient with solid carriers,optionally granulating a resulting mixture and processing the mixture orgranules, if desired or necessary after the addition of suitableexcipients, to form tablets or dragée cores.

Suitable carriers are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example tri-calcium phosphate or calciumhydrogen phosphate, and also binders, such as starch pastes using, forexample, corn, wheat, rice or potato starch, gelatin, tragacanth,methylcellulose and/or polyvinylpyrrolidone, and, if desired,disintegrators, such as the above-mentioned starches, and alsocarboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, oralginic acid or a salt thereof, such as sodium alginate. Excipients areespecially flow-conditioners and lubricants, for example silicic acid,talc, stearic acid or salts thereof, such as magnesium or calciumstearate, and/or polyethylene glycol. Dragée cores are provided withsuitable, optionally enteric, coatings, there being used inter aliaconcentrated sugar solutions which may contain gum arabic, talc,polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, orcoating solutions in suitable organic solvents or solvent mixtures or,for the preparation of enteric coatings, solutions of suitable cellulosepreparations, such as acetylcellulose phthalate orhydroxypropylmethylcellulose phthalate. Dyes or pigments may be added tothe tablets or dragée coatings, for example for identification purposesor to indicate different doses of active ingredient.

Other orally administrable pharmaceutical compositions are hard gelatincapsules and also soft, sealed capsules consisting of gelatin and aplasticiser, such as glycerol or sorbitol. The hard gelatin capsules maycomprise the active ingredient in the form of granules, for example inadmixture with fillers, such as lactose, binders, such as starches,and/or glidants, such as talc or magnesium stearate, and, if desired,stabilisers. In soft capsules the active ingredient is preferablydissolved or suspended in suitable liquids, such as fatty oils, paraffinoil or liquid polyethylene glycols, it is likewise being possible to addstabilisers.

Suitable rectally administrable pharmaceutical compositions are, forexample, suppositories that consist of a combination of the activeingredient with a suppository base material. Suitable suppository basematerials are, for example, natural or synthetic triglycerides, paraffinhydrocarbons, polyethylen glycols or higher alkanols. It is alsopossible to use gelatin rectal capsules which comprise a combination ofthe active ingredient with a base, material. Suitable base materialsare, for example, liquid triglycerides, polyethylenglycols or paraffinhydrocarbons.

The inhibitory effect on bone resorption of the inventive plant extractsand concentrates may be assessed by measuring the urinary excretion of[³H]-tetracycline from chronically prelabled rats as described in R. C.Mühlbauer and H. Fleisch, Am J Physiol 258, R 679-R689 (1990). Themethod is based on the characteristics (i) that ³H-labeled tetracyclineis deposited in hard tissues during their formation; and (ii) when boneis resorbed, [³H]-tetracycline is released, circulates in blood, and isexcreted into the urine where it can be assessed by counting ³H. This isprobably due to the fact that [³H]-tetracycline from bone circulates ina form that binds poorly to hydroxyapatite and, therefore,[³H]-tetracycline once liberated from bone, is only poorly reutilizedduring bone turnover, and because of an efficient renal excretion. Themethod may be performed as follows: rats are injected subcutaneouslytwice a week with increasing volumes of a solution containing[³H]-tetracycline starting shortly after birth until the age of aboutsix weeks. At the age of about 50 days, the animals are transferred toindividual metabolic cages and every rat is fed with the same amount ofa standardized diet for about the three weeks. After that, one group ofrats is fed with a purified diet, and another group is fed with thepurified diet containing in addition a certain amount of an inventiveplant concentrate or extract. During the experiments, the animals havefree access to demineralized water. When the rats are about 60 days old,daily 24-hour urine collections are started, and the ³H contents inurine are determined by liquid scintillation counting. A diagram is thenprepared wherein the [³H]-tetracycline contents in urine of the twogroups of rats are plotted as a function of time (days).

Experiments show that the plant extracts and concentrates of theinvention are capable of considerably decreasing the cumulative[³H]-tetracycline excretion in urine of intact male rats which indicatesa high inhibitory effect on bone resorption. Accordingly, the claimednutritional and pharmaceutical compositions are useful for the treatmentand prophylaxis of all kinds of diseases or conditions which arecharacterized by increased bone resorption, such as Paget's disease,tumor-induced bone disease or particularly osteoporosis.

The inhibitory effect of the plant extracts or concentrates on boneresorption may also be assessed by an in vitro assay in which ivoryslices, onto which freshly isolated osteoclasts have been settled, areincubated with a medium containing the extract or concentrate to betested. The inhibitory effect on osteoclasts is assessed by counting theosteoclast resorption pits on the ivory slice.

In the following Examples, which illustrate the invention, % are partsby weight unless stated otherwise, and temperatures are given in ° C.

EXAMPLE 1

The following is an example of a suitable composition of an inventivemedical nutrition supplement in powder form.

Supplement in Powder Form (1 portion) Content 65.0 g InventiveConcentrate¹⁾ 14.5 g including carbohydrates, protein and fiber Protein20.0 g including Ca-caseinate protein 8.7 g skim milk powder 11.0 g Fat2.8 g including omega-6 polyunsaturated acids 1.3 g omega-3polyunsaturated acids 0.03 g Carbohydrates (including inventive extract)31.0 g including lactose 16.5 g maltodextrin 3.5 g Fiber (soluble) 5.0 gFurther ingredients 3.0 g including Na 230 mg K 500 mg Ca 600 mg Mg 90mg P 430 mg Cl 350 mg Zn 150 mg Retinol (vitamin A) 0.3 mg Calciferol(vitamin D) 5.0 mcg Tocopherol (vitamin E) 3.0 mg Phylloquinone (vitaminK1) 30.0 mcg Thiamin (vitamin B1) 0.4 mg Riboflavin (vitamin B1) 0.5 mgPyridoxine (vitamin B6) 0.8 mg Cyanocobalamin (vitamin B12) 0.8 mcgAscorbic acid (vitamin C) 20.0 mg Biotin 50.0 mcg Folic acid 120.0 mcgNiacinamide 5.0 mg Panthothenic acid 2.0 mg Energy value 229 kcal ¹⁾Theinventive concentrate is obtained by drying 250 g fresh tomato andgrinding the dried tomato to a fine powder.

The above supplement may be mixed with water and taken in appropriateconcentration between meals.

EXAMPLE 2

The following is an example of a suitable composition of an inventiveFunctional Food in the form of a cereal bar.

Cereal Bar (1 portion = 2 bars of 32 g) Content 64.0 g Inventiveconcentrate¹⁾ 14.5 g Sorbitol 11.2 g Palm Oil 4.9 g Cornflake Crumbs 6.0g Rolled Oats 6.0 g Crisp Rice 6.0 g Gelatin 7.0 g Soy protein 7.0 gNa-chloride 0.7 g Ca 0.5 g Mg 0.2 g Calciferol (vitamin D) 5.0 mcg ¹⁾Theinventive concentrate is obtained by drying 250 g fresh tomato andgrinding the dried tomato to a fine powder..

EXAMPLE 3

Effect of Tomato Concentrate on Bone Resorption

The measurement of the effect of the inventive plant extracts andconcentrates on bone resorption is based on a method as described in R.C. Mühlbauer and H. Fleisch, Am J Physiol 259, R 679-R689 (1990). Boneresorption is monitored by the urinary excretion of ³H in Wistar ratsprelabled from birth for 6 weeks with [³H]-tetracycline as described inthe above-mentioned reference. The rats are then housed in individualmetabolic cages and are fed for 10 days with a standard laboratory chow(Kliba 331, Klingentalmühle, Kaiseraugst, Switzerland) containing 1.0 gCa, 0.7 g P, and 80 IU of vitamin D₃/100 g of food. After thisadaptation period, all rats receive a diet containing 1.0 g Ca, 1.2 g P,and 80 IU of vitamin D₃/100 g dry weight. This is achieved by addingappropriate amounts of Ca-gluconate and neutral phosphate salts to abasic low calcium, low phosphate diet (Sodi 2134, Klingenthalmühle,Kaiseraugst, Switzerland) in powder form for another 10 days duringwhich urine is collected. Then rats are “pair-fed” receiving 28 g of wetfood per day. One group (n=5) is switched to a purified diet (“Diet P”,Sodi 2160, Klingenthalmühle, Kaiseraugst, Switzerland given as wet foodwith a water content of 45±2% containing 1.0 g Ca, 1.2 g P, and 80 IU ofvitamin D₃/100 g dry weight), a second group (n=5) is fed with thepurified diet containing in exchange for 1 g of diet 1 g ground drytomato per day (corresponding to 17.2 gram of fresh tomato) and a thirdgroup (n=5) is fed with the purified diet containing in exchange for 1 gof diet 1 g ground dry onions per day (corresponding to 8.1 g freshonions).

After 10 days adaptation without urine collection and a further 10 dayswith urine collection, the rats are allocated to the different treatmentgroups. Using the baseline 24 hour [³H]-tetracycline excretion asselection criterion, special care is taken to obtain similar meaninitial values for each group. Thereafter, the rats are switched to thepurified diet with or without inventive concentrate and daily 24-hoururine collections are performed over a period of 10 days, and thecumulative [³H]-tetracycline excretion in urine is determined by liquidscintillation counting.

After 10 days of treatment the cumulative inhibition of bone resorptionwas 15%±4 and 26%±4, in rats daily fed the ground and dried tomato andonion respectively, measured as counts per minute of the control overcounts per minute of the tomato and onion group. Both values for the drytomato and dry onion fed groups were clearly outside the confidenceinterval of the control group. In other words, both dried tomato anddried onions showed significant inhibition of bone resorption. In thesame set-up, the values for groups fed 1 g dry soy, 1 g dry carrot or 1g skim milk powder were not outside the confidence interval, i.e. theseingredients did not show a significant inhibition of bone resorption atthe dosage of 1 g per day.

1. A method for decreasing bone resorption caused by a disease orcondition which causes bone resorption comprising administering to amammal including a human, in need thereof, a concentrate from a plant ofthe genus Lycopersicon, in an effective amount for inhibiting boneresorption wherein said concentrate is obtained by a process selectedfrom the group consisting of: a. drying or freeze-drying the plant andgrinding or granulating said dried or freeze-dried plant, and b.squeezing the plant to obtain a liquid fraction and drying said liquidfraction, wherein said concentrate is administered in an amount of 0.1to 20 grams per day.
 2. The method of claim 1 wherein said disease orcondition is Paget's disease, tumor inducing bone disease orosteoporosis.
 3. The method of claim 1 wherein said plant is selectedfrom the group consisting of Lycopersicon esculentum, Lycopersiconpimpinellifolium, Lycopersicon hirsutum, Lycopersicon peruvianum,Lycopersicon paviflorum and Lycopersicon pennellii.